Department of Biochemistry, College of Medicine, Chungbuk National University , Cheongju, South Korea.
Small GTPases. 2020 Jul;11(4):280-288. doi: 10.1080/21541248.2018.1435986. Epub 2018 Apr 20.
Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) (YAP/TAZ) are transcriptional coactivators that regulate genes involved in proliferation and transformation by interacting with DNA-binding transcription factors. Remarkably, YAP/TAZ are essential for cancer initiation or growth of most solid tumors. Their activation induces cancer stem cell attributes, proliferation, and metastasis. The oncogenic activity of YAP/TAZ is inhibited by the Hippo cascade, an evolutionarily conserved pathway that is governed by two kinases, mammalian Ste20-like kinases 1/2 (MST1/2) and Large tumor suppressor kinase 1/2 (LATS1/2), corresponding to 's Hippo (Hpo) and Warts (Wts), respectively. One of the most influential aspects of YAP/TAZ biology is that these factors are transducers of cell structural features, including polarity, shape, and cytoskeletal organization. In turn, these features are intimately related to the cell's ability to attach to other cells and to the surrounding extracellular matrix (ECM), and are also influenced by the cell's microenvironment. Thus, YAP/TAZ respond to changes that occur at the level of whole tissues. Notably, small GTPases act as master organizers of the actin cytoskeleton. Recent studies provided convincing genetic evidence that small GTPase signaling pathways activate YAP/TAZ, while the Hippo pathway inhibits them. Biochemical studies showed that small GTPases facilitate the YAP-Tea domain transcription factor (TEAD) interaction by inhibiting YAP phosphorylation in response to serum stimulation, while the Hippo pathway facilitates the YAP-RUNX3 interaction by increasing YAP phosphorylation. Therefore, small GTPase pathways activate YAP/TAZ by switching its DNA-binding transcription factors. In this review, we summarize the relationship between the Hippo pathway and small GTPase pathways in the regulation of YAP/TAZ.
Yes 相关蛋白 1（YAP）和转录共激活因子与 PDZ 结合基序（TAZ）（YAP/TAZ）是转录共激活因子，通过与 DNA 结合转录因子相互作用，调节参与增殖和转化的基因。值得注意的是，YAP/TAZ 是大多数实体瘤起始或生长所必需的。它们的激活诱导癌症干细胞属性、增殖和转移。YAP/TAZ 的致癌活性受到 Hippo 级联的抑制，Hippo 级联是一种进化上保守的途径，由两种激酶，哺乳动物 Ste20 样激酶 1/2（MST1/2）和大肿瘤抑制激酶 1/2（LATS1/2）控制，分别对应于“s Hippo（Hpo）和 Warts（Wts）。YAP/TAZ 生物学中最具影响力的方面之一是，这些因子是细胞结构特征的传感器，包括极性、形状和细胞骨架组织。反过来，这些特征与细胞附着在其他细胞和周围细胞外基质（ECM）的能力密切相关，也受到细胞微环境的影响。因此，YAP/TAZ 对整个组织层面发生的变化做出响应。值得注意的是，小 GTPases 作为肌动蛋白细胞骨架的主要组织者发挥作用。最近的研究提供了令人信服的遗传证据，表明小 GTPase 信号通路激活 YAP/TAZ，而 Hippo 通路抑制它们。生化研究表明，小 GTPases 通过抑制 YAP 在血清刺激下的磷酸化，促进 YAP-Tea 结构域转录因子（TEAD）的相互作用，从而激活 YAP/TAZ，而 Hippo 通路通过增加 YAP 的磷酸化来促进 YAP-RUNX3 的相互作用。因此，小 GTPase 途径通过切换其 DNA 结合转录因子来激活 YAP/TAZ。在这篇综述中，我们总结了 Hippo 通路和小 GTPase 通路在调节 YAP/TAZ 中的关系。
